The
n e w e ng l a n d j o u r na l
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m e dic i n e
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Planned Cesarean or Vaginal Delivery for Twin Pregnancy To the Editor: The Twin Birth Study reported by Barrett et al. (Oct. 3 issue)1 recruited women with a twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation. Women who delivered preterm made up just less than half the study groups. Many of the primary outcomes (fetal or neonatal death or serious neonatal morbidity) in both groups of the study would have been related to preterm birth and were unlikely to be preventable by cesarean delivery. In a previous study of data from England, Northern Ireland, and Wales, we analyzed 10 years of data on twins and concluded that the major determinant of neonatal death was the degree of prematurity, that the small additional risk associated with vaginal delivery was observed only at term, and that failure of future trials to exclude preterm births could mask a protective effect of cesarean delivery.2 Given these findings, it would be helpful to know the absolute risks, the relative risks, and the risk difference (plus the associated 95% confidence intervals) in the comparison of the planned-cesarean and planned-vaginal-delivery groups for births at term. Although it is unlikely that any statistically significant difference might be observed, knowing the possible range of effect of planned cesarean delivery could be useful in counseling women with twins about the method of delivery at term. Gordon C.S. Smith, Ph.D., D.Sc. University of Cambridge Cambridge, United Kingdom
Ian R. White, Ph.D. Medical Research Council Biostatistics Unit Cambridge, United Kingdom No potential conflict of interest relevant to this letter was reported. 1. Barrett JFR, Hannah ME, Hutton EK, et al. A randomized
trial of planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med 2013;369:1295-305.
2. Smith GC, Fleming KM, White IR. Birth order of twins and
risk of perinatal death related to delivery in England, Northern Ireland, and Wales, 1994-2003: retrospective cohort study. BMJ 2007;334:576-8.
DOI: 10.1056/NEJMc1314560
To the Editor: The trial by Barrett et al. is predicated on the emergence of thought (from data cited by the authors1 and an understanding of the mechanisms of hypoxic injury during vaginal delivery) that elective cesarean section reduces hazards to the fetus. Thus, examining whether a new highly vigilant strategy of vaginal delivery (with the option of emergency cesarean section within 30 minutes) does not lead to more complications than elective cesarean section would more appropriately have been performed as a noninferiority study of vaginal delivery, not a superiority study of elective cesarean section. Considering the seriousness of the primary outcome measure in this trial, the noninferiority margin of a noninferiority study should be set at an absolute minimum.2 The confidence interval around the risk associated this week’s letters 279
Planned Cesarean or Vaginal Delivery for Twin Pregnancy
280
Preventive Angioplasty in Myocardial Infarction
283
An Emmonsia Species Causing Disseminated Infection in South Africa
285
Surgical Skill and Complication Rates after Bariatric Surgery
286
Efficacy of Vemurafenib in Hairy-Cell Leukemia
n engl j med 370;3 nejm.org january 16, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHERN KENTUCKY UNIV on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
279
The
n e w e ng l a n d j o u r na l
with planned cesarean delivery, as compared with planned vaginal delivery (odds ratio 1.16; 95% confidence interval [CI], 0.77 to 1.74), does not convincingly rule out a clinically important increase in risk associated with vaginal delivery. Michael Keane, B.M., B.S. Swinburne University of Technology Melbourne, VIC, Australia [email protected] No potential conflict of interest relevant to this letter was reported. 1. Smith GCS, Pell JP, Dobbie R. Birth order, gestational age,
and risk of delivery related perinatal death in twins: retrospective cohort study. BMJ 2002;325:1004-9. 2. Scott IA. Non-inferiority trials: determining whether alternative treatments are good enough. Med J Aust 2009;190:326-30. DOI: 10.1056/NEJMc1314560
of
m e dic i n e
more detailed analysis involving women who underwent randomization at full-term gestation. The former would not be an intention-to-treat analysis and would need to be interpreted with caution. In response to Keane: we assumed that planned vaginal delivery was the standard of care, and therefore the trial was designed to test the superiority of planned cesarean delivery in reducing the probability of the primary outcome. The smallest clinically important difference to justify planned cesarean delivery was set at a relative risk of 0.5 (i.e., a reduction in the probability of the primary outcome from 4% to 2%). The confidence interval for the odds ratio (0.77 to 1.74) excludes by some margin the value of 0.5, since the odds ratio is a good estimate of the relative risk for such rare outcomes. Taking a Bayesian perspective with a noninformative prior distribution for the relative risk, one could state that the probability that the relative risk is 0.5 or less (i.e., that planned cesarean delivery is sufficiently superior to justify its routine adoption) is 0.00003. The protocol was reviewed by an expert panel for the funding agency, the Canadian Institutes of Health Research, and the manuscript underwent peer review before publication. In neither review was the idea raised that the trial should have been designed as a noninferiority study. Jon F.R. Barrett, M.B., B.Ch., M.D. Andrew R. Willan, Ph.D.
The Authors Reply: Smith and White hypothesize, on the basis of their previous analysis, that preterm birth had a substantial influence on the primary outcome in our study and that this obscures any potential effect of the method of delivery. In our study, the primary outcome occurred significantly less often in infants of women who underwent randomization at term than in infants of women who underwent randomization before term (odds ratio, 0.41; 95% CI, 0.21 to 0.81; P = 0.01). However, the test of the interaction between gestational age at randomization and treatment group did not reach statistical significance (P = 0.18). Therefore, the University of Toronto statistical analysis involving the subgroup of Toronto, ON, Canada women who underwent randomization at term K.S. Joseph, M.D., Ph.D. was not justified in the main article. University of British Columbia We are considering Smith and White’s sug- Vancouver, BC, Canada gestion regarding secondary analyses involving Since publication of their article, the authors report no furwomen who delivered at full-term (with adjust- ther potential conflict of interest. ment for potential confounders), as well as a DOI: 10.1056/NEJMc1314560
Preventive Angioplasty in Myocardial Infarction To the Editor: Wald et al. (Sept. 19 issue)1 report the results of the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) study, which showed that preventive percutaneous coronary intervention (PCI) reduced the risk of cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI). In this study, a patient with stenosis of 50% or more in a noninfarct artery was eligible for PCI. Unfortunately, 280
the authors do not report the severity and location of the stenoses or the left ventricular ejection fraction. The lack of such data may lead to a misinterpretation of the results of the study for several reasons. First, most studies concerning revascularization have defined clinically significant stenosis as a narrowing of the artery by at least 70%, except for the left main artery.2 Second, the prognosis for a patient with 90% steno-
n engl j med 370;3 nejm.org january 16, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHERN KENTUCKY UNIV on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Planned Cesarean or Vaginal Delivery for Twin Pregnancy To the Editor: The Twin Birth Study reported by Barrett et al. (Oct. 3 issue)1 recruited women with a twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation. Women who delivered preterm made up just less than half the study groups. Many of the primary outcomes (fetal or neonatal death or serious neonatal morbidity) in both groups of the study would have been related to preterm birth and were unlikely to be preventable by cesarean delivery. In a previous study of data from England, Northern Ireland, and Wales, we analyzed 10 years of data on twins and concluded that the major determinant of neonatal death was the degree of prematurity, that the small additional risk associated with vaginal delivery was observed only at term, and that failure of future trials to exclude preterm births could mask a protective effect of cesarean delivery.2 Given these findings, it would be helpful to know the absolute risks, the relative risks, and the risk difference (plus the associated 95% confidence intervals) in the comparison of the planned-cesarean and planned-vaginal-delivery groups for births at term. Although it is unlikely that any statistically significant difference might be observed, knowing the possible range of effect of planned cesarean delivery could be useful in counseling women with twins about the method of delivery at term. Gordon C.S. Smith, Ph.D., D.Sc. University of Cambridge Cambridge, United Kingdom
Ian R. White, Ph.D. Medical Research Council Biostatistics Unit Cambridge, United Kingdom No potential conflict of interest relevant to this letter was reported. 1. Barrett JFR, Hannah ME, Hutton EK, et al. A randomized
trial of planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med 2013;369:1295-305.
2. Smith GC, Fleming KM, White IR. Birth order of twins and
risk of perinatal death related to delivery in England, Northern Ireland, and Wales, 1994-2003: retrospective cohort study. BMJ 2007;334:576-8.
DOI: 10.1056/NEJMc1314560
To the Editor: The trial by Barrett et al. is predicated on the emergence of thought (from data cited by the authors1 and an understanding of the mechanisms of hypoxic injury during vaginal delivery) that elective cesarean section reduces hazards to the fetus. Thus, examining whether a new highly vigilant strategy of vaginal delivery (with the option of emergency cesarean section within 30 minutes) does not lead to more complications than elective cesarean section would more appropriately have been performed as a noninferiority study of vaginal delivery, not a superiority study of elective cesarean section. Considering the seriousness of the primary outcome measure in this trial, the noninferiority margin of a noninferiority study should be set at an absolute minimum.2 The confidence interval around the risk associated this week’s letters 279
Planned Cesarean or Vaginal Delivery for Twin Pregnancy
280
Preventive Angioplasty in Myocardial Infarction
283
An Emmonsia Species Causing Disseminated Infection in South Africa
285
Surgical Skill and Complication Rates after Bariatric Surgery
286
Efficacy of Vemurafenib in Hairy-Cell Leukemia
n engl j med 370;3 nejm.org january 16, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHERN KENTUCKY UNIV on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
279
The
n e w e ng l a n d j o u r na l
with planned cesarean delivery, as compared with planned vaginal delivery (odds ratio 1.16; 95% confidence interval [CI], 0.77 to 1.74), does not convincingly rule out a clinically important increase in risk associated with vaginal delivery. Michael Keane, B.M., B.S. Swinburne University of Technology Melbourne, VIC, Australia [email protected] No potential conflict of interest relevant to this letter was reported. 1. Smith GCS, Pell JP, Dobbie R. Birth order, gestational age,
and risk of delivery related perinatal death in twins: retrospective cohort study. BMJ 2002;325:1004-9. 2. Scott IA. Non-inferiority trials: determining whether alternative treatments are good enough. Med J Aust 2009;190:326-30. DOI: 10.1056/NEJMc1314560
of
m e dic i n e
more detailed analysis involving women who underwent randomization at full-term gestation. The former would not be an intention-to-treat analysis and would need to be interpreted with caution. In response to Keane: we assumed that planned vaginal delivery was the standard of care, and therefore the trial was designed to test the superiority of planned cesarean delivery in reducing the probability of the primary outcome. The smallest clinically important difference to justify planned cesarean delivery was set at a relative risk of 0.5 (i.e., a reduction in the probability of the primary outcome from 4% to 2%). The confidence interval for the odds ratio (0.77 to 1.74) excludes by some margin the value of 0.5, since the odds ratio is a good estimate of the relative risk for such rare outcomes. Taking a Bayesian perspective with a noninformative prior distribution for the relative risk, one could state that the probability that the relative risk is 0.5 or less (i.e., that planned cesarean delivery is sufficiently superior to justify its routine adoption) is 0.00003. The protocol was reviewed by an expert panel for the funding agency, the Canadian Institutes of Health Research, and the manuscript underwent peer review before publication. In neither review was the idea raised that the trial should have been designed as a noninferiority study. Jon F.R. Barrett, M.B., B.Ch., M.D. Andrew R. Willan, Ph.D.
The Authors Reply: Smith and White hypothesize, on the basis of their previous analysis, that preterm birth had a substantial influence on the primary outcome in our study and that this obscures any potential effect of the method of delivery. In our study, the primary outcome occurred significantly less often in infants of women who underwent randomization at term than in infants of women who underwent randomization before term (odds ratio, 0.41; 95% CI, 0.21 to 0.81; P = 0.01). However, the test of the interaction between gestational age at randomization and treatment group did not reach statistical significance (P = 0.18). Therefore, the University of Toronto statistical analysis involving the subgroup of Toronto, ON, Canada women who underwent randomization at term K.S. Joseph, M.D., Ph.D. was not justified in the main article. University of British Columbia We are considering Smith and White’s sug- Vancouver, BC, Canada gestion regarding secondary analyses involving Since publication of their article, the authors report no furwomen who delivered at full-term (with adjust- ther potential conflict of interest. ment for potential confounders), as well as a DOI: 10.1056/NEJMc1314560
Preventive Angioplasty in Myocardial Infarction To the Editor: Wald et al. (Sept. 19 issue)1 report the results of the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) study, which showed that preventive percutaneous coronary intervention (PCI) reduced the risk of cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI). In this study, a patient with stenosis of 50% or more in a noninfarct artery was eligible for PCI. Unfortunately, 280
the authors do not report the severity and location of the stenoses or the left ventricular ejection fraction. The lack of such data may lead to a misinterpretation of the results of the study for several reasons. First, most studies concerning revascularization have defined clinically significant stenosis as a narrowing of the artery by at least 70%, except for the left main artery.2 Second, the prognosis for a patient with 90% steno-
n engl j med 370;3 nejm.org january 16, 2014
The New England Journal of Medicine Downloaded from nejm.org at NORTHERN KENTUCKY UNIV on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
